The HVS in collaboration with GlaxoSmithKline (GSK), Rixensart, Belgium, has developed several candidate live attenuated HAV vaccines. One such candidate was modified to become the currently licensed GSK inactivated HAV vaccine. In addition, the HVS has developed a candidate recombinant hepatitis E vaccine that is highly promising and that has recently completed clinical trials. In studies to further characterize this candidate hepatitis E vaccine, we have performed extensive pre-clinical trials to determine the potency of the vaccine, the duration of protection, the optimum regimen for administration, its protective efficacy against homologous versus heterologous virus strains, its ability to prevent infection as well as hepatitis and the minimum antibody titer that was effective in preventing infection and hepatitis, respectively. In the clinical trial, the vaccine was 96% efficacious in preventing hepatitis E following three doses of vaccine and 87% efficacious following two doses. The vaccine had no detectable side effects. These results are outstanding for a vaccine. GSK is currently determining its plans for future manufacture and distribution of the vaccine.[unreadable] [unreadable] The study of HCV, including vaccine development, is complicated by the genetic heterogeneity of the virus, which has resulted in at least six major genotypes and many subtypes. Detecting and quantifying the virus requires different sets of primers for PCR amplification. We have developed real-time PCR assays for the six major genotypes and have compared their specificity and sensitivity with other published essays.[unreadable] [unreadable] Immunity to HCV is poorly understood and there is controversy over how complete and how long-lasting immunity to prior exposure of the virus is. Here, we have demonstrated that immunity to repeated exposure to HCV is genotype-specific, incomplete and relatively short-lived: even reexposure to the homologous virus can result in persistent infection.[unreadable] [unreadable] In other studies, GB virus-B (GBV-B) immunity was further studied. GBV-B is the closest relative to hepatitis C virus, which is very difficult to study because it is transmissible only to chimpanzees. In contrast, GBV-B is transmissible to tamarins, a species of New World monkey not considered to be endangered. Tamarins that had previously been infected with GBV-B were re-challenged with the same virus and shown to be immune to reinfection; this immunity was long-lived and apparently more complete than immunity to HCV in chimpanzees and humans.[unreadable] [unreadable] In 2008, in collaboration with Michael Houghton (formerly of Chiron Corp.), we tested sera from Chirons HCV vaccine trials in chimpanzees, Specifically, we tested serial sera from chimpanzees that had received Chirons E1-E2 dimer vaccine (derived from the HCV-1 strain) that had been expressed from mammalian cells. Testing was performed with pseudo-typed retrovirus particles bearing the envelope glycoproteins of each of the major HCV genotypes (HCVpp). The magnitude of the antibody response against HCVpp bearing the envelope glycoproteins of a heterologous genotype 1a strain (H77C) paralleled the degree of protection of the chimpanzees: those animals with a high titer of neutralizing antibody against HCVpp were protected, whereas those with a lower titer were not. In addition, the neutralizing antibody was broadly cross-reactive, also neutralizing principally HCVpp bearing envelope glycoproteins of HCV genotypes 4a, 5a and 6a as well as those bearing the envelope glycoproteins of genoytpe 1a (manuscript in preparation). [unreadable] [unreadable] We also tested in chimpanzees an HCV vaccine consisting of expressed HCV E1 protein, either with or without expressed HCV NS3 protein. The vaccine was manufactured by Innogenetics N.V. and was tested under a Cooperative Research and Development Agreement (CRADA) with the company. In contrast to the experience with the Chiron vaccine, none of the chimpanzees was protected from infection or from persistent infection and none had neutralizing antibody to HCV as measured with the HCVpp test. The decisive results of this study led to the abandonment of the E1 vaccine by Innogenetics.